The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations

Chuan Hsiang Huang, Diana Mandelker, Oleg Schmidt-Kittler, Yardena Samuels, Victor E Velculescu, Kenneth W Kinzler, Bert Vogelstein, Sandra B Gabelli, Mario L Amzel

Research output: Contribution to journalArticle

Abstract

PIK3CA, one of the two most frequently mutated oncogenes in human tumors, codes for p110α, the catalytic subunit of a phosphatidylinositol 3-kinase, isoform α (PI3Kα, p110α/p85). Here, we report a 3.0 angstrom resolution structure of a complex between p110α and a polypeptide containing the p110α-binding domains of p85α, a protein required for its enzymatic activity. The structure shows that many of the mutations occur at residues lying at the interfaces between p110α and p85α or between the kinase domain of p110α and other domains within the catalytic subunit. Disruptions of these interactions are likely to affect the regulation of kinase activity by p85 or the catalytic activity of the enzyme, respectively. In addition to providing new insights about the structure of PI3Kα, these results suggest specific mechanisms for the effect of oncogenic mutations in p110α and p85α.

Original languageEnglish (US)
Pages (from-to)1744-1748
Number of pages5
JournalScience
Volume318
Issue number5857
DOIs
StatePublished - Dec 14 2007

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Phosphatidylinositol 3-Kinases
Catalytic Domain
Phosphotransferases
Phosphatidylinositol 3-Kinase
Mutation
Oncogenes
Protein Isoforms
Peptides
Enzymes
Neoplasms
Proteins

ASJC Scopus subject areas

  • General
  • Medicine(all)

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The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations. / Huang, Chuan Hsiang; Mandelker, Diana; Schmidt-Kittler, Oleg; Samuels, Yardena; Velculescu, Victor E; Kinzler, Kenneth W; Vogelstein, Bert; Gabelli, Sandra B; Amzel, Mario L.

In: Science, Vol. 318, No. 5857, 14.12.2007, p. 1744-1748.

Research output: Contribution to journalArticle

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AU - Mandelker, Diana

AU - Schmidt-Kittler, Oleg

AU - Samuels, Yardena

AU - Velculescu, Victor E

AU - Kinzler, Kenneth W

AU - Vogelstein, Bert

AU - Gabelli, Sandra B

AU - Amzel, Mario L

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AB - PIK3CA, one of the two most frequently mutated oncogenes in human tumors, codes for p110α, the catalytic subunit of a phosphatidylinositol 3-kinase, isoform α (PI3Kα, p110α/p85). Here, we report a 3.0 angstrom resolution structure of a complex between p110α and a polypeptide containing the p110α-binding domains of p85α, a protein required for its enzymatic activity. The structure shows that many of the mutations occur at residues lying at the interfaces between p110α and p85α or between the kinase domain of p110α and other domains within the catalytic subunit. Disruptions of these interactions are likely to affect the regulation of kinase activity by p85 or the catalytic activity of the enzyme, respectively. In addition to providing new insights about the structure of PI3Kα, these results suggest specific mechanisms for the effect of oncogenic mutations in p110α and p85α.

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